Key messages:
• We do not know if combinations of two or more treatments (of medication, diet, and exercise) benefit people who have or are at risk of developing cachexia (disease-related wasting). This is because there are currently not enough robust studies in this area.
• We need future research to increase our confidence in the evidence by conducting better designed and larger studies.
What is cachexia?
Cachexia is a complex metabolic syndrome that occurs in people with long-term illnesses (known as chronic illnesses), such as cancer, HIV/AIDS, chronic kidney disease, heart disease, and chronic obstructive pulmonary disease (COPD).
People who have cachexia may:
• lose weight unintentionally;
• lose muscle;
• feel tired, weak, or both;
• lose their appetite.
Cachexia affects well-being and can be life-threatening.
How is cachexia treated?
Studies are investigating how to best manage cachexia with different treatments. These treatments can include medications, diet, and exercise, provided in a single (unimodal) or combined (multimodal) treatment. It is thought that due to the complex biology of cachexia, a combination of treatments may work in a complementary way (synergistically) to help improve the symptoms associated with cachexia and people's well-being, extend life, or both.
What did we want to find out?
We wanted to find out if combining at least two treatments (out of diet, exercise, and medication) helped to improve: physical function and strength; muscle loss; weight; well-being; appetite; fatigue; and biological indicators within the blood (biochemical markers). We also wanted to find out if these interventions were associated with any unwanted or harmful (adverse) effects.
What did we do?
We searched for studies that compared treatment combinations of diet, exercise and/or medication (where at least two treatments were used together) to: different combinations of treatments; a single treatment; or treatment as usual (standard care) in adults with cachexia or at risk of developing cachexia. We compared and summarised the results of the included studies. We rated our confidence in the evidence based on factors such as study methods and the number of people included.
What did we find?
We found nine studies that included a total of 926 adults, with an average age of 63 years. Just over half of participants (57%) were men. Studies took place around the world, including Europe (six studies), Turkey (one study), New Zealand (one study), and the USA (one study). One study included people with HIV/AIDS (average age 43 years; 35 of 50 people in the study were men); one study included people with COPD (average age 72 years; 20 of 28 people in the study were men); and one study included people with chronic kidney disease (average age 70 years; 11 of 21 in the study were men). Six studies included people with cancer (average age 64 years; 461 of 893 people in the studies were men). The studies lasted six weeks to two years.
The studies used combinations of treatments which could have included diet, exercise, and/or medication, where at least two treatments were used together, and compared these to:
• treatment as usual (1 study, 46 people);
• different combinations of treatments (4 studies, 192 people);
• a single treatment (6 studies, 802 people).
The studies did not provide enough robust evidence to determine if multimodal interventions are associated with benefits or harms in people with or at risk of cachexia.
What are the limitations of the evidence?
We are not confident in the evidence because not all the studies provided information about everything that we were interested in. Additionally, the studies used different ways of measuring results, and most of the studies included only small numbers of people.
Importantly, future studies may change the conclusions of this review.
How current is this review?
The evidence is current to June 2024.
The review found insufficient evidence to support or refute the use of multimodal interventions in managing cachexia. The certainty of the evidence was very low. Methodologically rigorous, well-powered RCTs with adequate interaction times are needed to assess the effectiveness of multimodal interventions in managing cachexia across chronic illnesses.
Cachexia (disease-related wasting) is a complex metabolic syndrome which occurs in people with chronic illnesses, including cancer, HIV/AIDS, kidney disease, heart disease, and chronic obstructive pulmonary disease (COPD). People with cachexia experience unintentional weight loss, muscle loss, fatigue, loss of appetite, and reduced quality of life. Multimodal interventions which work synergistically to treat the syndrome could lead to benefits.
To assess the benefits and harms of multimodal interventions aimed at alleviating or stabilising cachexia in people with a chronic illness.
We searched CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers in July 2024, together with reference checking, citation searching, and contact with study authors to identify studies.
We included randomised controlled trials (RCTs) in adults with or at risk of cachexia, comparing multimodal interventions combining two or more modalities (of pharmacology, nutrition, exercise) to treatment as usual, variation of the intervention, or unimodal intervention.
Two review authors independently screened potentially eligible studies, extracted data, and assessed risk of bias (RoB 1). Primary outcomes were physical function, strength, and adverse events. Secondary outcomes were body composition and weight, quality of life (QoL), appetite, fatigue, and biochemical markers. We assessed the certainty of evidence with GRADE.
We included nine studies with 926 adults (mean age: 63 years). Study sample sizes ranged from 20 to 332 participants. Six studies were conducted in Europe, and one each in Turkey, New Zealand, and the USA. There were six studies in people with cancer, and one each in people with COPD, chronic kidney disease, and HIV/AIDS. We judged four studies to be at an overall high risk of bias, and five at an overall unclear risk. All outcomes in all comparisons had very low-certainty evidence, downgraded once for risk of bias and/or indirectness and twice for imprecision.
Multimodal intervention (pharmacological, nutritional, and/or exercise) compared to treatment as usual
One cancer study randomised 46 participants, with 41 included in all analyses except adverse events. The study assessed outcomes immediately after treatment, lasting six weeks. Compared to treatment as usual, there is no clear evidence for an effect of a multimodal intervention on: physical function (mean difference (MD) −16.10 m, 95% confidence interval (CI) −79.06 to 46.86; 41 participants); strength (MD 3.80 kg, 95% CI −3.21 to 10.81; 41 participants); adverse events (risk ratio (RR) 1.36, 95% CI 0.70 to 2.65; 46 participants); body composition (MD 7.89 cm2, 95% CI −10.43 to 26.21; 41 participants); weight (MD 5.89 kg, 95% CI −1.45 to 13.23; 41 participants); appetite (MD 0.68 points, 95% CI −0.60 to 1.96; 41 participants); fatigue (MD 0.12, 95% CI −1.05 to 1.29; 41 participants); and biochemical markers (MD 2%, 95% CI 0.99 to 3.01; 41 participants), but the evidence was very uncertain; QoL was not reported.
Multimodal intervention compared to variation of the intervention
Three cancer studies and one HIV/AIDS study randomised 192 participants. We could not use the available data, nor obtain additional data, from two studies (one in cancer, one in HIV/AIDS). The studies assessed outcomes immediately after treatment, ranging from three to seven months. Compared to a variation of the intervention, there is no clear evidence for an effect of a multimodal intervention on: physical function (MD 10.0 m, 95% CI −36.27 to 56.27; 1 study, 56 participants); strength (MD 0.7 kg, 95% CI −3.75 to 5.15; 1 study, 56 participants); adverse events (RR 0.87, 95% CI 0.38 to 2.02; P = 0.75, I2 = 0%; 2 studies, 95 participants); body composition (MD −2.67 kg, 95% CI −5.89 to 0.54; P = 0.10, I2 = 0%; 2 studies, 95 participants); weight (MD −2.47 kg, 95% CI −7.11 to 2.16; P = 0.30, I2 = 0%; 2 studies, 95 participants); QoL (standardised mean difference (SMD) −0.15, 95% CI −0.55 to 0.26; P = 0.47, I2 = 0%; 2 studies, 95 participants); appetite (SMD −0.34, 95% CI −1.27 to 0.59; P = 0.48, I2 = 79%; 2 studies, 95 participants); fatigue (MD 6.40 points, 95% CI −1.10 to 13.90; 1 study, 56 participants); or biochemical markers (MD 9.80 pg/mL, 95% CI −6.25 to 25.85; P = 0.23, I2 = 73%; 2 studies, 95 participants), but the evidence is very uncertain.
Multimodal intervention compared to unimodal intervention
We included six studies (802 participants) in this comparison: three cancer studies, and one each in people with COPD, chronic kidney disease, and HIV/AIDS. The studies assessed outcomes immediately after treatment, ranging from three to seven months. We could not use the available data, nor obtain additional data, from the HIV/AIDS study. Compared to a unimodal intervention, there is no clear evidence for an effect of a multimodal intervention on: physical function (SMD 0.02, 95% CI −0.22 to 0.26; P = 0.86, I2 = 0%; 2 studies, 348 participants); strength (SMD 0.23, 95% CI −0.81 to 1.27; P = 0.66, I2 = 0%; 2 studies, 348 participants); adverse events (RR 0.87, 95% CI −0.43 to 1.73; P = 0.68, I2 = 45%; 2 studies, 395 participants); body composition (SMD 0.11, 95% CI −0.28 to 0.50; P = 0.58, I2 = 74%; 5 studies, 742 participants); body weight (SMD −0.02, 95% CI −0.38 to 0.33; P = 0.90, I2 = 49%; 4 studies, 431 participants); QoL (SMD 0.22, 95% CI −0.29 to 0.73; P = 0.39, I2 = 61%; 3 studies, 411 participants); appetite (SMD −0.09, 95% CI −0.58 to 0.40; P = 0.72, I2 = 58%; 2 studies, 395 participants); fatigue (MD −6.80 points, 95% CI −12.44 to −1.17; 1 study, 244 participants); and biochemical markers (SMD 0.11, 95% CI −0.59 to 0.80; P = 0.76, I2 = 79%; 3 studies, 411 participants), but the evidence is very uncertain.